Alcohol Withdrawal Symptoms.
In alcohol-dependent persons, cessation of drinking may lead to craving for alcohol and symptoms of alcohol withdrawal syndrome (AWS) (Victor, 1967, Chang, 2001, Bayard, 2004). These symptoms usually occur within 12 to 72 hours after the last drink and range in type, intensity, timing and frequency. The symptoms include tremor, anxiety, autonomic hyperactivity (sweating, increased blood pressure, tachycardia), hallucinations, seizures and delirium tremens (DT).
Alcohol Withdrawal Seizures.
Alcohol withdrawal (AW) seizures are considered a major AWS symptom together with DT and hallucinations. AW seizures are described as occurring in approximately 10% of people withdrawing from alcohol, being generalized tonic-clonic (95%), often multiple (60%), and usually occurring 7-48 hours after cessation of drinking (90%) (Victor, 1967). Most AW seizures are noted as having normal EEG (90%) and occurring within a period of 6 hours or less from first to last seizure (85% of patients). There is no reported gender or ethnic specificity of the seizures. The occurrence of AW seizures and DT in alcoholic patients requires immediate attention and treatment.
Pathophysiology of AWS and AW Seizures: Role of Ion Channels.
Chronic alcohol exposure is known to modify the neuronal expression of ion channels implicated in neurotransmission: ligand-activated, γ-aminobutyric (GABA)A and NMDA receptor-channels, and voltage-gated, L- and N-type Ca2+ channels. The effect of chronic alcohol on ion channels varies depending on the type of channel but overall, it leads to a state of hyperexcitability of the central nervous system and accounts for much of the neurological symptoms associated with alcohol withdrawal.
Pathophysiology of AWS and AW Seizures: Role of Ion Channels.
Acutely, ethanol affects many of the ion channels implicated in neurotransmission and brain function: ligand-activated (GABA and glutamate) receptor/channels, and voltage-gated ion channels (L-, N- and P/Q type Ca2+ channels). Chronically, ethanol leads to neuroadaptative changes in the activity and expression of these channels. It is currently believed that AW seizure is a manifestation of such changes, when ethanol is abruptly withdrawn (Crews, 1996; Metten, 1996).
Ligand-Gated Ion Channels—GABA and Glutamate Receptors.
Ethanol affects GABA-mediated neurotransmission and GABA receptors (Davies, 2003). Acutely, it enhances the stimulatory effect of GABA on GABAA receptors. In contrast, chronic exposure to alcohol modifies the subunit composition of the receptor and reduces the sensitivity of the channel to ethanol (Crews, 1996). It is believed that GABAA receptor stimulation contributes to the anxiolytic and sedative effect of ethanol whereas GABAA inhibition or desensitization to ethanol is anxiogenic and excitatory. The importance of GABAA receptors in the pathogenesis of AWS is underscored by the effectiveness of GABAA receptor agonists (e.g., benzodiazepines, barbiturates) in the treatment of AWS seizures.
Glutamate-activated receptors are excitatory, post-synaptic channels that are permeable to sodium and calcium. Their activation depolarizes the postsynaptic neuronal membrane and increases the probability of downstream firing. Acutely, ethanol antagonizes all three classes of glutamate receptors: N-methyl-D-aspartic acid (NMDA) receptors, AMPA and kainate receptors (Crews, 1996; Hoffman, 2003). In contrast, chronic exposure to ethanol leads to a compensatory increase in NMDA receptor expression and glutamate “supersensitivity.” NMDA receptor up-regulation is considered a key component of alcohol withdrawal and also a major contributor to ethanol-induced, Ca2+-mediated neuronal death. Thus the development of NMDA antagonists may be useful for reducing the acute symptoms of alcohol withdrawal as well as the excitotoxic brain damage associated with seizures, head trauma, and thiamine deficiency in alcoholics.
Voltage-Gated Ca2+ Channels.
There are several types of voltage-gated Ca2+ channels (Moreno, 2002; Lipscombe, 2002), all of which are sensitive to changes in membrane potential and allow calcium ions to flow in neurons when activated by action potentials. The channel-dependent calcium signals play a primary role in neurotransmitter release in the synaptic space, and also in the activation of intracellular calcium-sensitive processes. Three voltage-gated Ca2+ channel types have been recognized as playing a major role in both acute and chronic alcohol toxicity: the L-, the N- and the P/Q types. L-type Ca2+ channels are rather ubiquitously distributed in the CNS, and in many other tissues. In neurons, the L-type calcium channels are localized predominantly on cell bodies and proximal dendrites (Hell, 1993). They are thought to be involved in cell differentiation and gene activation, but have also been implicated in neurotransmission as indicated by the significant effect of L-type Ca2+ channel agonists and antagonist on AWS and alcohol-withdrawal seizures. N- and P/Q type Ca2+ channels are concentrated in presynaptic areas and play a significant role in the release of neurotransmitters from intracellular storage vesicles in the synaptic space.
L-Type Ca2+ Channels.
Acute exposure to ethanol blocks L-type voltage-gated Ca2+ channels. It is a slow-developing block with IC50 ranging from 10-200 mM and characterized by a reduction in open probability of the channel and a small hyperpolarizing shift in the steady state inactivation of the channel (Mullikin-Kirkpatrick, 1995). As observed with NMDA receptors, chronic exposure to ethanol leads to compensatory upregulation of the expression of L-type Ca2+ channels in the brain. This effect has been confirmed in many studies using tissue homogenates or hippocampal slices, and can be easily reproduced in vitro using PC12 cells (a clonal line of neural crest origin) cultured for several days in the presence of ethanol (Messing, 1986; Harper, 1989, Brennan, 1990 & 1991). The work by Guppy and colleagues (Guppy, 1995) is particularly interesting in that it shows that, in rats, alcohol-induced upregulation of the L-type channels (as determined by [3H]nitrendipine binding) occurs as early as 3 days in the brain cortex and is reversible. The study also shows that, if channel expression returns to normal within 24 hours after withdrawal, it has only decreased by 50% when seizures are maximum (6-8 hours post withdrawal) and ethanol has disappeared from the circulation. Taken together, the data suggest that enhanced L-type Ca2+ channel activity is a key factor in the onset of seizures in this model. Interestingly, there seems to be a relationship between genetic susceptibility to alcohol-induced seizures and genetic regulation of neuronal calcium channels in brain. Indeed, it was shown by Brennan and colleagues (Brennan, 1990) that mice selectively bred for severe withdrawal seizures (WSP) have a significantly greater up-regulation of brain L-type Ca2+ channels (assessed as [3H]nitrendipine binding sites) than mice resistant to withdrawal (WSR mice). Thus voltage-gated L-type Ca2+ channels are intimately associated with the onset of alcohol-induced seizures and AWS-related hyperexcitability. The mechanism by which up-regulation of L-type Ca2+ channels leads to hyperexcitability may simply be a direct increase in intraneuronal Ca2+ availability followed by enhanced neurotransmitter release. However, a recent study showed that nifedipine blocks ethanol-induced increased message expression of DBI, a diazepam binding inhibitor that colocalizes with GABA in synaptic vesicles (Mohri, 2003). This finding suggests that L-type Ca2+ channels may also contribute to hyperexcitability in AWS patients by secondarily decreasing GABAergic neurotransmission.
N- and P/Q Type Ca2+ Channels.
Less is known about the effect of ethanol on N- and P/Q type voltage-gated Ca2+ channels. However, a pattern similar to what has been reported for L-type voltage-gated Ca2+ channels (acute inhibition, chronic upregulation) emerges from the few studies that have examined the issue. Wang et al. (Wang, 1991), using rat neurohypophysis preparations, reported an inhibitory effect of ethanol on N-type Ca2+ channels. More recently, Solem and colleagues reported that ethanol inhibits N-type and P/Q-type Ca2+ channel dependent Ca2+ signaling in nerve growth-factor (NGF) treated PC12 cells (Solem, 1997). The effect of ethanol on P-type currents has not been consistently observed though, and in rat Purkinje neurons, P-type currents appear insensitive to ethanol (Hall, 1994). In contrast to its acute effect, chronic ethanol up-regulates N- and P-type Ca2+ channels, both in vitro (PC12 cells, McMahon, 1999) and in vivo (mouse, McMahon, 1999; rat, N'Gouemo, 2003). Interestingly, the effect of ethanol on mouse brain (cortex, hippocampus) N-type Ca2+ channels is significant after 3 days of exposure to ethanol, a time when animals are prone to seizures upon withdrawal (McMahon, 1999). Also, the effect of chronic ethanol on P-type Ca2+ channels was demonstrated in the inferior colliculus, a part of the brain and neural network implicated in audiogenic seizures following ethanol withdrawal. Thus, both N- and P-type Ca2+ channels play a significant role in the pathogenesis of AWS-related seizures and, like L-type Ca2+ channels, they are putative molecular targets for anti-withdrawal medications.
Other Ion Channels.
Other ion channels including strychnine-sensitive glycine receptors, nicotinic receptor ion channels and 5-hydroxytryptamine receptor channels have been recognized as potential players in alcohol toxicity and may be implicated in AWS seizures. These channels too are putative targets for new AWS medications.
Current Treatments for AWS, and Limitations Thereof.
A number of drugs have been used in the treatment of AWS and related seizures: neuroleptic compounds, beta adrenergic antagonists, alpha adrenergic agonists (clonidine), carbamazepine, barbiturates. However, at this time the drugs of choice in the U.S. are the benzodiazepines (for review see Mayo-Smith, 1997; Saitz, 1997; and Myrick, 1998).
Some studies have demonstrated the efficacy of barbiturates in reducing signs and symptoms of withdrawal. Phenobarbital in particular, has well-documented anticonvulsive activity, can be administered by oral, intramuscular and intravenous routes and has a low abuse potential. However, like other barbiturates, it poses a risk of respiratory depression, particularly when combined with alcohol, and has an overall lower safety profile than benzodiazepines when used at high doses. Both benzodiazepines and barbiturates have been shown to exhibit cross-dependence with alcohol (in fact, that is why they work to suppress withdrawal) and are also abused by humans (Litten & Allen, 1991). Many lines of evidence suggest that some genes mediating withdrawal seizures from alcohol also mediate withdrawal from other central nervous system depressants (Metten, 1994, 1998, 1999; Buck, 1997, 1999; Fehr, 2002).
Beta-adrenergic antagonists may be useful in reducing the autonomic manifestations of withdrawal such as elevated blood pressure. However, there is no indication that these compounds are effective in reducing seizures during withdrawal. Further, these compounds are known to increase the risk for delirium.
Antiepileptic medications (e.g., carbamazepine and valproic acid) have been successfully used to treat alcohol withdrawal for many years in Europe. Carbamazepine in particular was found to be superior to barbiturate and oxazepam for patients with mild to moderate withdrawal, and thus may provide a reasonable alternative to benzodiazepines.
Neuroleptic agents, including phenothiazines and haloperidol show effectiveness in reducing certain signs and symptoms of withdrawal (hallucinations). However, they are less effective than benzodiazepines in preventing delirium tremens and seizures, and can induce epileptic seizures by decreasing seizure threshold.
Current Treatments for AWS, and Limitations Thereof.
A number of drugs have been used in the treatment of AWS and related seizures: neuroleptic compounds, beta adrenergic antagonists, alpha adrenergic agonists (clonidine), carbamazepine, barbiturates. However, at this time the drugs of choice in the U.S. are the benzodiazepines (for review see Mayo-Smith, 1997; Saitz, 1997; and Myrick, 1998).
Some studies have demonstrated the efficacy of barbiturates in reducing signs and symptoms of withdrawal. Phenobarbital in particular, has well-documented anticonvulsive activity, can be administered by oral, intramuscular and intravenous routes and has a low abuse potential. However, like other barbiturates, it poses a risk of respiratory depression, particularly when combined with alcohol, and has an overall lower safety profile than benzodiazepines when used at high doses. Both benzodiazepines and barbiturates have been shown to exhibit cross-dependence with alcohol (in fact, that is why they work to suppress withdrawal) and are also abused by humans (Litten & Allen, 1991). Many lines of evidence suggest that some genes mediating withdrawal seizures from alcohol also mediate withdrawal from other central nervous system depressants (Metten, 1994, 1998, 1999; Buck, 1997, 1999; Fehr, 2002).
Beta-adrenergic antagonists may be useful in reducing the autonomic manifestations of withdrawal such as elevated blood pressure. However, there is no indication that these compounds are effective in reducing seizures during withdrawal. Further, these compounds are known to increase the risk for delirium.
Antiepileptic medications (e.g., carbamazepine and valproic acid) have been successfully used to treat alcohol withdrawal for many years in Europe. Carbamazepine in particular was found to be superior to barbiturate and oxazepam for patients with mild to moderate withdrawal, and thus may provide a reasonable alternative to benzodiazepines.
Neuroleptic agents, including phenothiazines and haloperidol show effectiveness in reducing certain signs and symptoms of withdrawal (hallucinations). However, they are less effective than benzodiazepines in preventing delirium tremens and seizures, and can induce epileptic seizures by decreasing seizure threshold.
Currently, benzodiazepines, a class of compounds that activates GABA receptors are the recommended treatment of alcohol withdrawal particularly when associated with seizures. However, agents that target the other ion channels may also be useful as withdrawal-specific medications.
Therefore, while a limited number of drugs are currently available (e.g., benzodiazepines, antiepileptic and neuroleptic agents), current understanding of AWS pathophysiology suggests that signaling pathways not targeted by these drugs, but implicated in AWS, may also be legitimate targets for medication development to treat alcohol withdrawal.
As discussed above, chronic administration of ethanol induces upregulation of brain L-type Ca2+ channels. These channels are the target of dihydropyridine L-type Ca2+ channel antagonists, a class of compound used for the treatment of high blood pressure. Experimentally, calcium channel antagonists prevent ethanol-induced up-regulation of the L-type Ca2+ channels (Brennan, 1990; Whittington, 1991a), and suppress the development of hippocampal hyperexcitability to ethanol (Whittington, 1991a,b). Other studies have shown that acute administration of nimodipine and nitrendipine block withdrawal seizures in the animal (Bone, 1989; Little, 1986; Littleton, 1990). More recently (Watson, 2002), it was shown that the antiseizure activity of Ca+ channel antagonists were selective for alcohol withdrawal seizures (no prevention of bicuculline or pentylenetetrazol-induced convulsions). Collectively, however, while current animal data suggests that calcium channel antagonists may be useful in the treatment of AWS in humans, only a few clinical studies have been conducted, showing either a moderate beneficial effect (Altamura, 1990; Shulman 1998) or no effect (Banger, 1992). Thus, the efficacy of calcium channel blockers in treating AWS, remains to be confirmed in humans, and significantly, the dihydropyridine calcium channel antagonists used in the Altamura and Shulman studies, are very selective compounds that act exclusively on L-type Ca2+ channels.
Therefore, there is a pronounced need in the art for more effective treatment of AWS in humans. It is possible that calcium channel blockers with a larger spectrum of activity (i.e., active on more than one class of voltage-gated Ca2+ channels) would be more effective in the treatment of AWS.
Convulsive Seizure.
Periodic unpredictable occurrences of seizures are commonly associated with epilepsy. The two main types of epileptic seizures are partial seizures and generalized seizures.
Partial seizures are characterized as those that affect neurons limited to part of one cerebral hemisphere, and may be accompanied by impairment of consciousness.
Generalized seizures include those in which both hemispheres are involved and consciousness is usually impaired. Generalized seizures include absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures and atonic seizures (see, e.g., Dreifuss et al., Classification of Epileptic Seizures and the Epilepsies and Drugs of Choice for Their Treatment, p. 1-9, In: Antiepileptic Drugs: Pharmacology and Therapeutics, Eds M. J. Eadie and F. J. E. Vajda; Wilder et al., Classification of Epileptic Seizures, p. 1-13, In: Seizure Disorders, A Pharmacological Approach to Treatment, Raven Press, New York (1981); McNamara, Drugs Effective in the Therapy of Epilepsies, p. 476-486, In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed., Eds P. B. Molinoff, R. W. Ruddon (1996)).
Pseudoepileptic or non-epileptic seizures can be caused by a definable medical condition, for example, cardiovascular disease including arrhythmias, aortic stenosis, severe hypertension and orthostatic hypotension; toxic or metabolic disorders including hypoglycemia and drug toxicity; or sleep disorders. Non-epileptic seizures can also be induced by psychiatric conditions, e.g., hysteria, schizophrenia.
Thus, convulsions or seizures can result from disorders or specific conditions, e.g., epilepsy, acquired immunodeficiency syndrome (AIDS), Parkinson's disease, Alzheimer's disease, other neurodegenerative disease including Huntington's chorea, schizophrenia, obsessive compulsive disorders, tinnitus, neuralgia, trigeminal neuralgia, post-traumatic epilepsy, intoxication or withdrawal from barbiturates, brain illness or injury, brain tumor, choking, drug abuse, electric shock, fever (especially in young children), head injury, heart disease, heat illness, high blood pressure, meningitis, poisoning, stroke, toxemia of pregnancy, uremia related to kidney failure, venomous bites and stings, withdrawal from benzodiazepines, febrile convulsions, and afebrile infantile convulsions.
Therefore, there is a pronounced need in the art for more effective treatment of not only of AWS in humans, but also of convulsive seizure. It is possible that calcium channel blockers with larger spectrum of activity (i.e., active on more than one class of voltage-gated Ca2+ channels) would be more effective in the treatment of convulsive seizure.